In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor. L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluRs) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors. At present, eight different members of these mGluRs' are known and of these some even have sub-types. On the basis of structural parameters, the different second messenger signaling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III. Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain. Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression. Indications which are potentially treatable with mGluR1 agonists include Alzheimer's disease, cognitive disorders and memory deficits, Huntington's chorea, amyotrophic lateral sclerosis (ALS), and dementia.
Selective positive allosteric modulators (enhancers) of mGlu1 receptors are compounds which do not directly activate mGlu1 receptors by themselves, but binding of these compounds increase the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Positive allosteric modulation is an attractive mechanism for enhancing appropriate physiological receptor activation, and the results obtained in cerebellar slices strongly suggest that mGluR1 enhancers can modulate physiological mGlu1 activity in the brain [Knoflach et al., Proc. Nat. Acad. Sci. USA 98:13402–13407 (2001)] by increasing the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Selective mGluR1 enhancers therefore possess important therapeutic utility and their discovery opens the possibility for therapeutically relevant positive modulation of mGlu1 receptors.